Processes and intermediates useful in the preparation of flutroline

Abstract

1,1-Di(p-fluorophenyl)urea, 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, an efficient process for converting the former to the latter, further comprising conversion of the latter to 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (flutroline) or to 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (an alternative flutroline intermediate).

I claim: 
     
       1. A process for preparing 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, which comprises the steps of (a) chlorinating 1,1-di(p-fluorophenyl)urea with a (C 1  -C 4 )alkyl hypochlorite in a step (a) reaction-inert solvent to form a first intermediate, 3-chloro-1,1-di(p-fluorophenyl)urea, in situ;   (b) rearranging the intermediate 3-chlorourea by the action of an alkali metal (C 1  -C 3 )alkoxide in a step (b) reaction-inert solvent to form a second intermediate, 2-(C 1  -C 3 )carbalkoxy-1,1-di(p-fluorophenyl)hydrazine, in situ;   (c) hydrolyzing and decarboxylating the intermediate carbalkoxyhydrazine with water in the presence of base in a step (c) reaction-inert solvent to form a third intermediate, 1,1-di(p-fluorophenyl)hydrazine, in situ;   (d) condensing the intermediate 1,1-di(p-fluorophenyl)hydrazine with N-carbobenzoxy-4-piperidone in the presence of a strong acid in a step (d) reaction-inert solvent, and recovering said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.   
     
     
       2. A process of claim 1 wherein the (C 1  -C 4 )alkyl hypochlorite is t-butyl hypochlorite. 
     
     
       3. A process of claim 1 wherein the alkali metal alkoxide is sodium methoxide and the second intermediate is 2-carbomethoxy-1,1-(p-diphenyl)hydrazine. 
     
     
       4. The process of claim 3 wherein the (C 1  -C 4 )alkyl hypochlorite is t-butyl hypochlorite. 
     
     
       5. A process of claim 1 wherein the strong acid is hydrochloric acid. 
     
     
       6. A process of claim 4 wherein the strong acid is hydrochloric acid. 
     
     
       7. A process of claim 1 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst to form 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 
     
     
       8. A process of claim 4 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst at 0°-75° C. to form 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 
     
     
       9. A process of claim 8 wherein the noble metal is palladium. 
     
     
       10. A process of claim 9 wherein the hydrogen pressure is 2 to 8 atmospheres. 
     
     
       11. A process of claim 6 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst at 0°-75° C. to form 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 
     
     
       12. A process of claim 11 wherein the noble metal is palladium. 
     
     
       13. A process of claim 12 wherein the pressure of hydrogen is 2-8 atmospheres. 
     
     
       14. A process of claim 1 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst in the presence of substantially one molar equivalent of 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran, at 0°-75° C. in a reaction-inert solvent, to form flutroline. 
     
     
       15. A process of claim 4 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst in the presence of substantially one molar equivalent of 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran, at 0°-75° C. in a reaction-inert solvent to form flutroline. 
     
     
       16. A process of claim 6 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst in the presence of substantially one molar equivalent of 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran, at 0°-75° C. in a reaction-inert solvent to form flutroline. 
     
     
       17. A process of claim 16 wherein the noble metal is palladium. 
     
     
       18. A process of claim 17 wherein the hydrogen pressure is 2 to 8 atmospheres.